The Door

Image source

Opaque as the Agency's process may appear to non-life sciences investors like me, and obviously highly generalized as my analogy below is, it's an understatement to say Provectus' past, present and future has been, is and will be more about the process (with current emphasis on the step of finally generating randomized clinical trial data). This is especially so for a molecule like PV-10 and Provectus' approach to treating cancer, the former being very novel and the latter being historically unsuccessful (i.e., treating the disease locally in order to defeat it locally and then [in so doing] systemically).

A door is built when a company achieves a consensus design for a pivotal Phase 3 trial with the FDA. The door is closed of course, but with its design and construction complete the drug company can commence a registration study in pursuit of the key the regulator holds to open it. A successful study that also leads to drug approval yields the key from the Agency to unlock the door, opening into the room of a market opportunity for the company to commercialize its therapeutic. Drugs fall down before they reach their doors' respective thresholds by failing their pivotal studies, and thus they're unable to get the key.

Unremarkably and yet, I suppose, obviously, designing and building the door, traveling the path to secure the key from the FDA, opening of the door, and entering the room are just parts of or steps in the Agency's process. Everyone does not follow the process all of the time. When they do, and if they are successful, the process works. The FDA's process could be observed as almost agnostic to the drug going through it.

1986. After a cursory review of the literature, the first I/O door that appears to have been designed, constructed, unlocked and opened was Interferon alpha (IFN-α) [1].

2010. The second I/O door built and unlocked could be for Provenge (sipuleucel-T) [2].

One could argue for other doors such as Bacillus Calmette-Guérin's (BCG) approval in 1990, Herceptin [trastuzumab] in 1998, Gardasil in 2006, and Xgeva [denosumab] in 2010.

2011. The third door might be for Bristol-Myers' anti-CTLA-4 agent Yervoy (ipilimumab). Pfizer's tremelimumab, a related compound, fell down before the threshold by failing its pivotal Phase 3 trial.

2014. The fourth and fifth doors then would be those for anti-PD-1 agents Keytruda (Merck U.S.' pembrolizumab) and Opdivo (Bristol's nivolumab).

Other similar doors may be designed, constructed and unlocked for companies entering pivotal trials of their anti-PD-1 or anti-PD-L1 agents. One also might consider Perjeta's (pertuzumab) approval in 2012.

2015. A sixth door has been designed and built for but currently remains unlocked to Amgen's talimogene laherparepvec (T-Vec).

April's 22-1 advisory committee vote in favor of the drug should encourage the FDA to give Amgen the key in or by October 27th (the drug's PDUFA date). This outcome, while probable, is not certain. Unlocking T-Vec's door, irrespective of the debate about the size of the room into which the opened door permits entry, could and should be a catalyst (in context) for PV-10. 

Provectus' CTO Dr. Eric Wachter, PhD designed and built PV-10's door last year and this year for melanoma (specifically, unresectable locally advanced cutaneous melanoma) by working with the FDA to achieve a consensus pivotal study design. In so doing he convinced the regulator the drug could be a viable treatment option for patients if the trial successfully meets its endpoints.

For Provectus unlocking T-Vec's door could substantially further discussion about or potentially lead to a license, co-development and/or collaboration deal with and/or an minority equity investment by Big Pharma. The issuance of the joint Pfizer-Provectus combination therapy patent allowed in April, more pivotal melanoma Phase 3 site activations, and/or the presentation/publication of Moffitt Cancer Center's PV-10 mechanism of action study also could contribute to the discussion or potentially lead to a deal or deals.

T-Vec and PV-10's doors are similar and different. While T-Vec's door is similar to those of Yervoy, Keytruda and Opdivo in that they have metastatic melanoma labels, PV-10's door possesses the different feature of treating patients at an earlier stage of the melanoma disease cycle. Its pivotal study embraces the potentially more profound outcome of being the local agent with the opportunity to prove that, delivered locally, PV-10 can forestall, prevent or stop the spread of the systemic disease that is cancer (melanoma).

[1] FDA-Approved Cancer Immunotherapies and CRI’s Impact, April 9, 2015, Alexandra Mulvey
[2] Issues Impacting Stakeholder Adoption of Immuno-Oncology, February 16, 2015, AJMC, Dr. Bruce Feinberg, DO

The "Immuno-Oncology" Market That Encompasses $PVCT & PV-10

On May 15, a Wall Street Journal article highlighted middle market investment bank Leerink Swann's of immuno-oncology addressable market as an annual $20 billion figure. A week later, Citigroup analyst Andrew Baum was quoted by Reuters sizing the market as $35 billion a year over the next 10 years for, where this category of drugs would be used in some way in the management of up to 60% of all cancers. I think the immuno-oncology category includes immuntherapies broadly, but it's possible the above estimates are inclusive only of anti-CTLA-4, anti-PD1 and anti-PDL-1 (and the like) agents.

I Think it's a Good Time to be a $PVCT Shareholder

Shareholders are closer to the end-game for the stock than to their journey's beginning. The company's  life sciences technology is head and shoulders above its peers. The lead compound presents a compelling clinical value proposition capable, perhaps, of indeed shifting the paradigm of cancer treatment (and treatment of inflammatory skin disorders). The drug already is productized, with a product business proposition to match that of the underlying technology. Provectus appears to be nearing transparency regarding regulatory clarity for oncology. The company also appears to be nearing certain license deals that will provide initial market validation. In sum, management, Provectus and its shareholders are nearing the end-game.

Provectus' technology is a game changer, productized to effect the change, and can be delivered and scaled to profit from the change to come.

The technology, PV-10 for oncology, is an effective local treatment capable of as effectively treating distant disease and visceral metastases. The drug, through expression of antigens in context in tumors into which PV-10 is injected fortifies the immune system against cancerous agents. Immunization occurs because PV-10's chemoablation causes rapid, complete, durable necrosis of tumor lesions.

"Scientists have been trying for decades to understand why the body's immune system didn't see cancer cells as the enemy and attack them. Recent discoveries revealed that tumors are adept at cloaking themselves by hijacking the body's own mechanism for preventing the system's T-cells, the infection- and disease-fighting cells of the immune system, from running amok against healthy tissue."

The above quote from Wall Street Journal (WSJ) article New Cancer Drugs Harness Power of Immune System (5/15/13) is not quite on-point. Rather, the quote below from Bloomberg article Human Immune-Boosting Cancer Drugs Seen Extending Lives (5/12/13) is more to the point.

"Now many believe that by strengthening the immune system’s ability to identify and kill cancer cells, they can broaden the attack so it will fight any dangerous malignancy. “You’re setting up a fair fight” with the disease, said Nils Lonberg, a senior vice president at Bristol-Myers, in a telephone interview. “The immune system is just as adaptable as the cancer.”"

How do you strengthen the immune system? Medical science has done it before with infectious diseases. Immune systems can be overwhelmed and, thus, are unable to help the human body fight back. Antibiotics themselves do not cure patients of infectious diseases that have afflicted them. Rather, the immune system cures the hosts with the help of antibiotics. Treating infectious diseases requires that antibiotics should have near absolute specificity for the infectious agent. Tough infections require multiple agents.

I think it's a good time to be a Provectus shareholder.

The volume of the conversations about immunotherapy has grown much, much louder. Take Xconomy's Luke Timmerman's article Genentech Follows Fast at ASCO as Cancer Immunotherapy Picks Up (5/15/13) for example.

"Genentech made its name in cancer by creating targeted antibody drugs that zero in on tumor cells while mostly sparing healthy tissue. Now it’s seeking to compete in the next wave of cancer immunotherapies, which are designed to spark the immune system to attack tumors like a virus."

Or take NBC's Nightly News report Immunotherapy targets cancer cells with remarkable results (5/15/13).

"Cancer cells typically put up a chemical shield to protect against the body’s disease-fighting T cells. But immunotherapy can break down the shield and let the T cells get to work."

The more the biopharmaceuticals industry, investing community and general public talk about immunotherapy, the better the environment or atmosphere for PV-10 and Provectus to flourish.

From the same WSJ article above: "More broadly, Leerink [Swann, a middle market investment bank] believes the "immuno-oncology" drug market could amount to a $20 billion category annually, putting it on a par with the cholesterol-lowering statin market at its height."

From dendritic cells (Dendreon's Provenge) to antitumor antibodies (Bristol-Myers' anti-CTLA-4 agent Yervoy) to immune checkpoint blockades (ASCO 2013's anti-PD1 and anti-PDL-1 agents):

"The immunotherapy of cancer has made significant strides in the past few years due to improved understanding of the underlying principles of tumor biology and immunology...[t]he pillars of human cancer therapy have historically been surgery, radiotherapy, and chemotherapy, but a fourth modality of immunotherapy has been well documented since 1890..." (Kirkwood et al.).

Big Pharma is tacking closer to the ultimate goal, but they mostly still are sailing wide of the objective.

"If the new generation of immune therapies lives up to its promise, “this is going to be a paradigm shift for treating cancer,” said Merck senior vice president Gary Gilliland in an interview. “We are pretty good at shrinking tumors, but not good at getting rid of them. Immune therapy is a way to begin to approach that.”"

Yes, Big Pharma is pretty good at shrinking cancerous tumors, but not yet good enough at making them go away.

Craig's postulation that you treat cancer like you treat an infectious disease requires a/the drug treatment to possess near absolute specificity for diseased tissue (spare normal tissue and clear rapidly from it) and induce a host response (combined apoptosis-autophagy of treated targets because intralesional delivery produces a “vaccine-like” systemic effect that enhances normal human body defenses) over a very wide range of activity (broad spectrum antibiotic-like)


PV-10 chemoablation causes rapid, complete, durable necrosis of tumor lesions.

I think it's a good time to be a Provectus shareholder.

The general discourse at the moment about immunotherapies, however, is far from well understood or a consensus. Take last week's exchange on Adam Feuerstein's Twitter feed @adamfeuerstein below.

Feuerstein had been explaining the fundamental bear case for Vical's Allovectin-7, but aside from perhaps some valid trial design questions, his "red flags" included a lack of positive statements by melanoma experts and institutional healthcare investors as well as a lack of immune-related toxicity by Allovectin-7. Church is not a fan of immune-related toxicity because of the long-term dangers of altering the immune system in order to use it. All of this despite the on-point replies of other respondents: directing T-cells to attack tumors rather than a broad uncontrolled response, the beauty of local treatment is limited toxicity, revolutionary if the local treatment works on visceral mets, etc.

Many monoclonal immunotherapies do cause terrible toxicities, which are related not just related to "taking the brakes off" the immune system. Their target antigens are not only on/in the immune cells they wish to suppress. Just like chemotherapy agents, immunotherapy agents also can cause collateral damage with more adverse side effects like cancer and death.

The nature of the conversation Feuerstein, Church and the others need to have has to be deeper and more substantive. It's too simplistic to say Allovectin-7 does or will not work. Whether it's Allovectin-7 or talimogene laherparepvecone (T-Vec, formerly OncoVEX), or PV-10 itself, one has to balance positive effects with side effects. Think of it as a biological signal-to-noise ratio. One can titer up dosages until one sees bad things happen.

I think Pfizer probably refused to do this with its anti-CTLA-4 agent tremelimumab, which is why it has a greater failure record in clinical trials than it's Bristol-Myers' ipilimumab. Bristol-Myers probably had a higher tolerance for "bad things to happen" in order to suss out the optimal or near-optimal signal-to-noise or benefit-to-side-effect ratio.

Remind yourself of Provectus' combination therapy work at AACR 2013 utilizing PV-10 and a systemic anti-CTLA-4 antibody. The highest dose of the latter killed the murine subjects more quickly. Lower doses were less effective but also less dangerous. Interestingly, the results the company concluded that while PV-10 is highly effective when all existing tumor is accessible for injection, for visceral or other inaccessible disease the combination of PV-10 with CTLA-4 blockade has important potential synergy. Nevertheless, the apparent toxicity at high doses of the anti-CTLA-4 antibody markedly reduced the effect of the antibody alone and the combination of PV-10 and the antibody.

If an immunotherapy is working, there has to be some response (e.g., inflamation, redness, blistering, itching, etc.). These "side effects" come with the territory, and merely are signs the immune system is now in the game. So, while one indeed is generating a toxic response by recruiting the immune system, the key is focusing this toxicity as much as possible.

The problem with Yervoy, and perhaps immunotherapies like anti-PD-1, anti-PDL-1 agents and other treatments, is the collateral damage they cause to the body. PV-10's great strength has been and is its ability to the target only what it kills and kill only what it targets. Another strength is the drug's ability to generate a very specific, targeted, immune response with very little collateral damage to anything but the tumor itself. So, some blistering occurs, body temperature rises, etc. Nothing more.

I think it's a good time to be a Provectus shareholder.

Still, regulatory clarity has to become transparent. Is it an MM Phase 3 trial under SPA powered for for a 6-month progressional free survival for PV-10 vs. 2-month plus PFS for the comparator DTIC?Or is it breakthrough designation therapy and accelerated approval or another accelerated pathway?

Further still, commercial validation through one or more meaningful license transactions (global, regional, dermatology) is required. For example, will it be Hisun-Pfizer Pharmaceuticals in China? Or another company or entity? The Hisun-Pfizer joint venture was established in 2012 to sell off-patent medicines in China and other emerging markets. But economics are economics. Pfizer's 49% equity ownership and thus 49% ownership of any PV-10 sales in China would be a strong inducement to widening the entity's mandate through a license deal with Provectus.

Who will it be in India? In Japan? When will PH-10 be licensed, and to whom?

Provectus is squarely in the eye of key cancer patient advocates. The company participated in Melanoma Research Alliances' (MRA's) Fifth Annual Scientific Retreat in February. In April Peter joined MRA's President and CEO Wendy Selig, LiveSTRONG's President and CEO and Provectus corporate advisory board member Doug Ulman, Moffitt Cancer Research Center's Dr. Shari Pilon-Thomas and some media for dinner.

Key opinion leaders like Moffitt's Dr. Jeff Weber and Dr. Vernon Sondak and Pfizer's Dr. Craig Eagle are enthused about PV-10 as both a monotherapy and combination therapy.

More data is on the way. And data is driving and will drive the deals.

Yes, I think it's a good time to be a Provectus shareholder.